Opposite Effects With and Without Iron

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Science's STKE  10 Jan 2006:
Vol. 2006, Issue 317, pp. tw474
DOI: 10.1126/stke.3172006tw474

The lipocalin 24p3 binds to siderophores (microbial iron chelators) that bind iron and through this interaction can deliver iron to cells. Devireddy et al. identified the 24p3 receptor (24p3R), which resembles a 12-transmembrane cation transporter. Hela cells engineered to express 24p3R bound 24p3 and internalized it. When the cells were exposed to holo24p3 (complexed with iron-bound siderophore), intracellular iron concentrations were increased. When cells were exposed to apo24p3, which lacked iron, the intracellular concentration of iron decreased. When cells expressing 24p3R were labeled with radioactive iron, addition of apo24p3 resulted in the accumulation of iron in the culture medium that was coprecipitated with antibodies against 24p3. Thus, apo24p3 bound iron (presumably bound to an endogenous siderophore) and transported the iron out of the cell upon recycling of the receptor-holo24p3 complex. Consistent with transit through the recycling endosome, accumulation of labeled iron in the medium was blocked in cells expressing mutant versions of endosomal proteins (Rab11 and Rififylin) that inhibit recycling. 24p3 was released from cells regardless of whether the cells expressed the receptor. However, only 24p3 from the conditioned medium of cells expressing 24p3R was competent to bind radiolabeled iron, suggesting that newly synthesized 24p3 is not bound to an iron-binding protein but acquires this iron-binding protein after being internalized. Addition of apo24p3 to cells expressing the receptor resulted in increased abundance of the proapoptotic protein Bim and apoptosis, whereas holo24p3 did not induce apoptosis. Concomitant addition of transferrin to replenish the diminished cellular iron blocked apo24p3-induced apoptosis, indicating that apoptosis was the result of the decreased iron concentration. Finally, the authors show a connection between 24p3 and cancer caused by the BCR-ABL oncoprotein. In BCR-ABL cells, expression of 24p3R is repressed and the cells are refractory to the apoptotic effects of 24p3, despite showing an increase in 24p3 production. The chemotherapeutic agent imatinib, which inhibits BCR-ABL, inhibited the expression of the gene encoding 23p4 and increased the expression of the gene encoding 24p3R, thus resensitizing the cells to 23p4. The importance of iron in the apoptotic response of BCR-ABL to imatinib was confirmed by rescue of cells from imatinib-induced apoptosis by addition of holotransferrin. Thus, the 24p3 pathway appears to play a key role in iron homeostasis, and conditions that stimulate the production of apo24p3 result in loss of cellular iron and stimulation of apoptosis through increased production of proapoptotic Bim (see Richardson for commentary).

L. R. Devireddy, C. Gazin, X. Zhu, M. R. Green, A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 123, 1293-1305 (2005). [PubMed]

D. R. Richardson, 24p3 and its receptor: Dawn of a new iron age? Cell 123, 1175-1177 (2005). [PubMed]

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